Updated evidence-based (S3) European Dermatology Forum guideline on the use of topical corticosteroids in pregnancy

Developed by the Guideline Subcommittee “Topical Corticosteriods” of the

European Dermatology Forum

Subcommittee Members: Prof. Dr. Ching Chi-Chi, Taoyuan (Taiwan) Dr. Gudula Kirtschig, Tübingen (Germany Prof. Dr. Werner Aberer, Graz (Austria) Prof. Dr. Jean-Paul Gabbud, Bern (Switzerland) Prof. Dr. Jasna Lipozenčić, Zagreb (Croatia) Prof. Dr. Sarolta Kápáti, Budapest (Hungary) Prof. Dr. Uwe-Frithjof Haustein, Leipzig (Germany) Prof. Dr. Fenella Wojnarowska, Oxford (United Kingdom) Prof. Dr. Dr. Torsten Zuberbier, Berlin (Germany) Members of EDF Guideline Committee: Prof. Dr. Werner Aberer, Graz (Austria) Prof. Dr. Dieter Metze, Muenster (Germany) Prof. Dr. Martine Bagot, Paris (France) Prof. Dr. Gillian Murphy, Dublin (Ireland) Prof. Dr. Nicole Basset-Seguin, Paris (France) PD Dr. Alexander Nast, Berlin (Germany) Prof. Dr. Ulrike Blume-Peytavi, Berlin (Germany) Prof. Dr. Martino Neumann, Rotterdam (Netherlands) Prof. Dr. Lasse Braathen, Bern (Switzerland) Prof. Dr. Tony Ormerod, Aberdeen (United Kingdom) Prof. Dr. Sergio Chimenti, Rome (Italy) Prof. Dr. Mauro Picardo, Rome (Italy) Prof. Dr. Alexander Enk, Heidelberg (Germany) Prof. Dr. Annamari Ranki, Helsinki (Finland) Prof. Dr. Claudio Feliciani, Rome (Italy) Prof. Dr. Johannes Ring, Munich (Germany) Prof. Dr. Claus Garbe, Tübingen (Germany) Prof. Dr. Berthold Rzany, Berlin (Germany) Prof. Dr. Harald Gollnick, Magdeburg (Germany) Prof. Dr. Rudolf Stadler, Minden (Germany) Prof. Dr. Gerd Gross, Rostock (Germany) Prof. Dr. Sonja Ständer, Münster (Germany) Prof. Dr. Michael Hertl, Marburg (Germany) Prof. Dr. Wolfram Sterry, Berlin (Germany) Prof. Dr. Dimitrios Ioannides, Thessaloniki (Greece) Prof. Dr. Eggert Stockfleth, Bochum (Germany) Prof. Dr. Gregor Jemec, Roskilde (Denmark) Prof. Dr. Alain Taieb, Bordeaux (France) Prof. Dr. Lajos Kemény, Szeged (Hungary) Prof. Dr. George-Sorin Tiplica, Bucharest (Romania) Dr. Gudula Kirtschig, Tübingen (Germany) Prof. Dr. Elke Weisshaar, Heidelberg (Germany) Prof. Dr. Robert Knobler, Vienna (Austria) Prof. Dr. Sean Whittaker, London (United Kingdom) Prof. Dr. Annegret Kuhn, Muenster (Germany) Prof. Dr. Fenella Wojnarowska, Oxford (United Kingdom) Prof. Dr. Marcus Maurer, Berlin (Germany) Prof. Dr. Christos Zouboulis, Dessau (Germany) Prof. Dr. Kai Munte, Rotterdam (Netherlands) Prof. Dr. Dr. Torsten Zuberbier, Berlin (Germany)

Chairman of EDF Guideline Committee: PD Dr. Alexander Nast, Berlin (Germany)

Expiry date: 06/2019

EDF Guidelines Secretariat to PD Dr. Nast: Bettina Schulze, Klinik für Dermatologie, Venerologie und Allergologie, Campus Charité Mitte, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany phone: ++49 30 450 518 062, fax: ++49 30 450 518 911, e-mail: bettina.schulze@charite.de

1

Croatian Academy of Medical Sciences, Zagreb, Croatia

Updated evidence-based (S3) European Dermatology Forum guideline on

the use of topical corticosteroids in pregnancy

Running head: Updated guideline on topical steroids in pregnancy

C-C. Chi,*† G. Kirtschig,‡ W. Aberer,§ J.-P. Gabbud,¶ J. Lipozenčić, S.**

Kárpáti,†† U-F. Haustein,‡‡ F. Wojnarowska,§§ and T. Zuberbier¶¶

*Department of Dermatology and Centre for Evidence-Based Medicine, Chang Gung

Memorial Hospital, Chiayi, Chiayi, Taiwan

†College of Medicine, Chang Gung University, Taoyuan, Taiwan

‡Department of General Medicine and Interdisciplinary Care, University of Tübingen,

Tübingen, Germany

§Department of Dermatology, University of Graz, Graz, Austria

¶Dermatology and Venereology, Bern, Switzerland

** Croatian Academy of Medical Sciences, Zagreb, Croatia

††Department of Dermatology, Venereology and Dermato-oncology, Semmelweis

University, Budapest, Hungary

‡‡Department of Clinical and Experimental Dermatology, University of Leipzig, Leipzig,

Germany

§§Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK

2

¶¶Allergy-Centre-Charité, Department of Dermatology and Allergy, Charité-

Universitätsmedizin Berlin, Berlin, Germany

Corresponding author

Prof Dr med Dr h c Torsten Zuberbier

Department of Dermatology and Allergy

Charité - Universitätsmedizin Berlin

Charitéplatz 1

D-10117 Berlin

Tel. +49 30 450 518 135

Fax +49 30 450 518 919

E-mail: Torsten.Zuberbier@charite.de

Funding source: none

Conflict of interest: TZ, institutional funding for research and/or honoria for lectures

and/or consulting from Allergopharma, Ansell, Bayer Schering, DST, Faes Pharma,

Fujisawa, HAL, Henkel, Kryolan, Leti Pharma, Menarini, Merck, MSD, Novartis, Procter

& Gamble, Ranbaxy, Sanofi-Aventis, Schering Plough, Stallergenes, Takeda, and UCB;

the others, none.

3

What’s already known about this topic?

Only limited data on the fetal effects of topical corticosteroids are available.

What does this study add?

Mild/moderate topical corticosteroids are preferred to potent/very potent ones for use

in pregnant women. Use of potent/very potent topical corticosteroids, especially when

the applied amounts are large, is associated with an increased risk of low birth weight.

The current evidence does not support associations of maternal use of topical

corticosteroids with birth defect, preterm birth, and fetal death.

In the choice of the topical corticosteroids, also the risk benefit needs to be assessed

regarding cutaneous side effects for the mother with a higher risk of older topical

corticosteroids in comparison to more modern ones with a better therapeutic index.

4

Summary

Topical corticosteroids may be needed for treating skin conditions in pregnancy.

Nevertheless, only limited data on the fetal effects of topical corticosteroids are available.

A guideline subcommittee of the European Dermatology Forum was organised to update

an evidence-based guideline on the safe use of topical corticosteroids in pregnancy. The

current best evidence is from an updated Cochrane Review which included 14

observational studies with 1,601,515 study subjects and found no significant associations

between maternal use of topical corticosteroids of any potency and some adverse

pregnancy outcomes including mode of delivery, birth defect, preterm delivery, and fetal

death. However, maternal use of potent/very potent topical corticosteroids, especially in

large amounts, is associated with an increased risk of low birth weight. We conclude that

mild/moderate topical corticosteroids should be preferred to potent/very potent ones in

pregnancy and that the well-known topical side effects of corticosteroids on the mother’s

side need to be in the focus of the choice.

5

Introduction

Topical corticosteroids are frequently prescribed for treating various dermatoses

including eczema,1 psoriasis,2 discoid lupus erythematosus,3 and bullous pemphigoid.4

Women with these dermatoses may need topical corticosteroid treatment during

pregnancy. Pregnant women with specific dermatoses of pregnancy, for example atopic

eruption of pregnancy, need topical corticosteroid treatment as well.5 Nevertheless, the

effects of topical corticosteroids on the fetus are largely unclear. Drug references for

example the British National Formulary do not provide explicit instructions on

prescribing topical corticosteroids in pregnancy.6 A typical labelling for use of topical

corticosteroids in pregnancy is: “should be used during pregnancy only if the potential

benefit justifies the potential risk to the fetus.”7

Clinical decisions are usually a trade-off between conceivable benefit and harm.

The lack of knowledge on the safety of topical corticosteroids in pregnancy may result in

physicians’ hesitancy and non- or under-prescribing. Pregnant women’s over-concern of

fetal risk may lead to underuse of topical corticosteroids and decreased therapeutic

effects.8 A previous survey of 250 directors of departments of dermatology across Europe

found 30% were concerned about prescribing topical corticosteroids to pregnancy women

and 91% restrained their prescribing.9

For making an informed clinical decision on the use of topical corticosteroids in

pregnancy, an evidence-based guideline is warranted. We organised a guideline

subcommittee of the European Dermatology Forum and have developed an evidence-

based (S3) guideline on the use of topical corticosteroids in pregnancy in 2011.10 Herein

we present an updated guideline in which we added and appraised new evidence

6

Disclaimer

This guideline was developed by the European Dermatology Forum (available at

http://www.euroderm.org/edf/index.php/edf-guidelines/category/5-guidelines-

miscellaneous). The recommendations reflect the best data available at the time when this

guideline was prepared. Caution should be exercised in interpreting the data; the results

of future studies may require alteration of the conclusions or recommendations in this

report. It may be necessary or even desirable to depart from these recommendations in

special circumstances. Just as adherence to guidelines may not constitute defence against

a claim of negligence, so deviation from them should not be necessarily deemed

negligent.

Levels of evidence and grades of recommendation

Much has been written in recent years on the need for clinical guidelines and the criteria

they should meet for development and application, as well as evidence and

recommendations to be used in their support. We used the levels of evidence defined by

the Oxford Centre for Evidence-Based Medicine (Table 1)11 and the Grading of

Recommendations Assessment, Development and Evaluation (GRADE) Working

Group’s approach to rate the quality of evidence (Table 2).12 The quality of evidence

from randomised trials is initially rated as high and observational studies as low. Further

evaluation may upgrade the quality of evidence for large magnitude effect, dose response,

and confounders likely minimise the effect, and may downgrade due to study limitations,

imprecision, inconsistency of results, indirectness of evidence and publication bias.12

7

Evidence for harm from animal studies

Animal experiments showed corticosteroids have fetotoxic effects and are teratogenic.

Administration of systemic corticosteroids resulted in cleft palate in rabbits, mice, rats,

and hamsters.13-16 The occurrence of genital organ anomalies in mice correlated with the

amounts of corticosteroids applied to the eyes.17 Administration of dexamethasone in

juvenile rhesus monkeys resulted in permanent loss of hippocampal neurons, elevated

plasma cortisol levels at the circadian baseline and post-stress concentrations.18 The birth

weight of fetal lambs reduced after prenatal administration of betamethasone in a dose-

response relationship.19

One animal experiment illustrated that after application on the mothers’ skin,

appreciable levels of betamethasone 17, 21-dipropionate were detected in the fetal blood

of mice and rabbits.20 Animal studies have found topical corticosteroids are also

teratogenic. Diflorasone diacetate cream caused cleft palate after applied to pregnant rats’

skin at a dose of 0.001 mg/kg/day, which was just one-third of the equivalent human

topical dose. The treated rats had a higher rate of fetal death than untreated controls when

the dose was increased to 0.5 mg/kg/day.21 After topical application of diflorasone

diacetate 0.016 mg/kg/day to pregnant rabbits, depressed fetal growth, external anomalies

(31.9%), cleft palate (22.2%), and visceral defects (45.5%) were found.22

To sum up, animal experiments demonstrated that topical application of topical

corticosteroids to pregnant rodents resulted in teratogenic effects, low birth weight, and

increased fetal death, but these experiments cannot be extrapolated to humans as the

8

stratum corneum of the animals is much thinner and the percutaneous absorption is much

higher than in humans.

Pharmacology and pharmacokinetics in the mother

The systemic effects of topical corticosteroids rely on the degree of percutaneous

absorption and the pharmacokinetic pathways for systemically absorbed corticosteroids.

Corticosteroids are bound to plasma proteins, metabolised mainly in the liver, excreted in

the kidney, and cross the placenta in pregnant women.

Skin absorption and bioavailability of topical corticosteroids in pregnancy

The systemic effects of topical corticosteroids largely depend on the extent of

percutaneous absorption, which varies from < 0.5 to 7% when applied to intact skin23,24

and also on systemic bioavailability (see Figure 1). The degree of percutaneous

absorption, and hence the potential for systemic exposure, depends upon the following

factors:25

the nature of the corticosteroid chemical compound;

the nature of the vehicle;

the integrity of the skin barrier;

the use of occlusion;

the surface area and regional anatomic variation of the treated skin;

the frequency and duration of application ;

the metabolism of corticosteroids;

inflammation and/or other diseases in the skin;

9

pregnancy (there may be variation in different trimesters).

Hydrocortisone and other corticosteroids have various systemic bioavailability

following topical application due to different lipophilicity, degradability, and other

pharmacokinetic properties. Hydrocortisone, the least potent corticosteroid, is able to

suppress the adrenals following long-term use in children with dermatitis.26 Clobetasol

propionate ointment, the most potent topical corticosteroid, may cause adrenal

insufficiency at a very low dose of 2 g per day for 1 week.23 Adrenal suppression after

application of newer topical lipophilic corticosteroids (i.e. mometasone furoate,

fluticasone propionate, and methylprednisolone aceponate) under extreme conditions

have been documented,27,28 but was not found for mometasone furoate under more

moderate conditions (10 g/day)29 or in psoriatic patients (15 g/day).30

Previous studies found no significant differences in treatment response with once

or twice daily application of very potent corticosteroids. Likewise, there was no

difference or only a slight difference with once or twice daily application of potent or

moderately potent corticosteroids.31

The vehicle may enhance penetration and promote systemic absorption.25 The use

of occlusive dressings, hydration of skin, application over large surface areas, and

prolonged use can enhance systemic absorption.25 Percutaneous penetration is increased

over thin skin including the face, intertriginous areas, and genital area.25

Inflammation and other conditions of the skin may enhance percutaneous

absorption of topical corticosteroids. The percutaneous absorption of 1% hydrocortisone

cream during flares of eczema increased to 11 to 31 times that in remission.32 While only

10

< 0.5% of applied methylprednisolone aceponate was absorbed through intact skin,

removal of the skin barrier by stripping increased the absorption to 15.4 ± 7.7%.24

The change in the hydration and blood flow of the skin in pregnancy may alter the

systemic bioavailability of topical corticosteroids.33 Nevertheless, there have been no

studies on the systemic bioavailability of topical corticosteroids in pregnant women for

ethical concerns.

The data from nasal and inhaled corticosteroids may not be directly applicable to

the skin. The systemic bioavailability of fluticasone propionate and mometasone furoate

through these routes is very low;34-36 however, the data could not be directly extrapolated

to cutaneous application. The newer lipophilic corticosteroids including fluticasone

propionate, mometasone furoate, and methylprednisolone aceponate, should perhaps be

preferred based on fewer local and systemic side effects,37,38 but direct evidence from

pregnant women is lacking. However, these newer corticosteroids do have a better risk-

benefit profile regarding cutaneous side effects (Figure 1)39 and are maybe preferable due

to this benefit. In addition, they have been marketed for over 20 years and used

worldwide in a very high number of patients, giving further indirect evidence for safety

by the lack of reported side effects.

Metabolism of corticosteroids

Over 90% of absorbed corticosteroids in the plasma reversibly combine with two plasma

proteins: corticosteroid-binding globulin (CBG) and albumin. Only unbound

corticosteroids can enter cells to exert actions. Most of circulating corticosteroids are

bound at normal or low plasma levels. At higher plasma levels of corticosteroids, the

11

binding capacity of proteins is overwhelmed, and a greater proportion of the

corticosteroids are in the free form.40 A specific circumstance of physiological

hypercorticism happens in pregnancy. The high circulating oestrogen levels promote the

production of CBG, resulting in elevated total plasma cortisone levels. The physiological

significance of these changes during pregnancy on exogenous corticosteroids is unclear.41

Corticosteroids are metabolised in the liver to water-soluble compounds which are

excreted by the kidneys.40

Placental metabolism

The fetal effects of corticosteroids reply on their extent of transplacental passage (Table

3). The key metabolising enzyme of corticosteroids in the placenta is 11β-hydroxysteroid

dehydrogenase (11βHSD) that transforms biologically active cortisol (hydrocortisone)

into biologically inactive cortisone. Therefore, 11βHSD is the gatekeeper in limiting the

quantities of maternal cortisol that pass through the placenta to enter the fetus and in

protecting the fetus from unwanted harm.42 Hydrocortisone is assumed safe for use in

pregnancy because of the weak potency and high metabolism in the placenta. However,

one study using the fetal-placental unit before abortion found 15% of 3H-cortisol passed

through the placenta without being metabolised43 and another study illustrated a linear

relationship between maternal and fetal serum cortisol levels.44,45 Only 10-12% of

prednisolone passed through the placenta.46 In the meanwhile, dexamethasone,

methylprednisolone, and betamethasone are less metabolised by the placenta, and 67%,

45%, and 30% reached the fetus, respectively.47 Fluticasone propionate and budesonide

are unmetabolised,48 and thus high amounts of them pass through the placenta. To the

12

best of our knowledge, there is a lack of relevant studies on other corticosteroids.

However, the newer corticosteroids like mometasone, which shows a first-pass effect in

the liver, are most unlikely to pass the placenta in significant levels, if - like in other

corticosteroids - a linear relationship between the maternal and the fetal serum may be

assumed. In addition, mometasone is strongly bound to plasma proteins and the free

fraction is approximately 10-20 times lower compared to other corticosteroids49 which

should lead to lower transition into the placenta.

Evidence from human studies

The data available as to possible fetal harm from the use of topical corticosteroids in

pregnancy were limited. The current best evidence is from a recently updated Cochrane

review published in 2015.50 The review authors systematically searched 10 databases

including the Cochrane Skin Group Specialised Register, the Cochrane Pregnancy and

Childbirth Group Specialised Register, the Cochrane Central Register of Controlled

Trials, MEDLINE, EMBASE, LILACS, and five trial registers. They identified 14

relevant studies, including 5 cohort and 9 case-control studies which covered a total of

1,601,515 subjects (Table 4).51-63 A pregnant woman coauthor has been invovled in

preparing this review.

Most of the available data were related to orofacial cleft (level of evidence: 3).

The majority of the included studies found no significant associations between maternal

use of topical corticosteroids and adverse pregnancy outcomes including mode of

delivery, birth defect, preterm delivery, and fetal death, although these studies all had

certain limitations.51-60,62 A significant association between topical corticosteroids and

13

orofacial cleft was found in one small case-control study,61 while none of other included

studies showed a similar effect. Two cohort studies showed a significant association

between maternal use of potent/very potent topical corticosteroids and low birth

weight.59,63 One further study identified an increased risk of low birth weight when the

dispensed amounts of potent/very potent topical corticosteroids were more than 300 g

during pregnancy.60

Conclusions

The available data on the safety of topical corticosteroids in pregnancy suggest a lack of

associations of their use by the mother with birth defect, preterm birth, fetal death, and

mode of delivery. Limited evidence does suggest a significant association of maternal use

of potent/very potent topical corticosteroids, especially in large amounts, with low birth

weight.59,60,63 However, the finding was from only two research groups. Further studies

are warranted for reproducing this finding.

Recommendations

1. Mild/moderate topical corticosteroids should be used in preference to more potent

corticosteroids in pregnancy (low-quality evidence).

2. Potent/very potent topical corticosteroids should be used as second-line therapy for

as short a time as possible. Once daily application of potent/very potent topical

corticosteroids is recommended. Appropriate obstetric care should be provided as

they increase the risk of low birth weight (low-quality evidence).

14

3. The association between maternal exposure to potent/very potent topical

corticosteroids and fetal growth restriction needs to be considered when applying

them during pregnancy. However, systemic corticosteroids have a greater

bioavailability than that of topical corticosteroids, and thus have a greater potential

for fetotoxicity than topical corticosteroids (systemic corticosteroids are associated

with a reduction in fetal birth weight and an increase in preterm delivery64,65), and

should not be used in preference (low-quality evidence).

4. On theoretical grounds the danger of adverse events is increased when areas with

high absorption (e.g. genitals, eyelids, flexures) are treated (very low-quality

evidence).

5. There are no data available to determine if newer lipophilic topical corticosteroids

(mometasone furoate, fluticasone propionate, and methylprednisolone aceponate,)

with a good therapeutic index (Figure 1) are associated with a smaller risk of low

birth weight. On theoretical grounds a favourable side effect profile for the use in

pregnancy is suggested, furthermore they have the practical advantage of once daily

application compared to older preparations (very low-quality evidence).

Advice to women about using topical corticosteroids in pregnancy

1. Women can be reassured that there is no significantly increased risk of birth defect,

preterm delivery, and fetal death while using topical corticosteroids for medical

indications in pregnancy. There is also no increased risk of low birth weight when

using mild/moderate topical corticosteroids in pregnancy.

2. Women should be informed that there is a small risk for low birth weight when

15

using large amounts of potent/very potent topical corticosteroids in pregnancy, but

this risk is less than that of systemic corticosteroids, for an additional risk for

miscarriage and preterm delivery associated with use of systemic corticosteroids.65

3. Depending on the severity of their skin conditions, pregnant women should use

topical corticosteroids of the least potency required and limit the use amounts,

preferably once daily. Pregnant women should be cautious on sites of high

percutaneous absorption for example the skin folds, armpits, and vulva.

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21

47 Miller NM, Williamson C, Fisk NM et al. Infant cortisol response after prolonged

antenatal prednisolone treatment. BJOG 2004; 111: 1471-4.

48 Murphy VE, Fittock RJ, Zarzycki PK et al. Metabolism of synthetic steroids by

the human placenta. Placenta 2007; 28: 39-46.

49 Hochhaus G. Pharmacokinetic/pharmacodynamic profile of mometasone furoate

nasal spray: potential effects on clinical safety and efficacy. Clin Ther 2008; 30:

1-13.

50 Chi CC, Wang SH, Wojnarowska F et al. Safety of topical corticosteroids in

pregnancy. Cochrane Database Syst Rev 2015; 10: CD007346.

51 Carmichael SL, Ma C, Werler MM et al. Maternal corticosteroid use and

hypospadias. The Journal of pediatrics 2009; 155: 39-44, .e1.

52 Czeizel AE, Rockenbauer M. Population-based case-control study of teratogenic

potential of corticosteroids. Teratology 1997; 56: 335-40.

53 Mygind H, Thulstrup AM, Pedersen L et al. Risk of intrauterine growth

retardation, malformations and other birth outcomes in children after topical use

of corticosteroid in pregnancy. Acta Obstet Gynecol Scand 2002; 81: 234-9.

54 Källén B. Maternal drug use and infant cleft lip/palate with special reference to

corticoids. Cleft Palate Craniofac J 2003; 40: 624-8.

55 Pradat P, Robert-Gnansia E, Di Tanna GL et al. First trimester exposure to

corticosteroids and oral clefts. Birth Defects Research 2003; 67: 968-70.

56 Carmichael SL, Shaw GM, Ma C et al. Maternal corticosteroid use and orofacial

clefts. Am J Obstet Gynecol 2007; 197: 585.e1-.e7.

22

57 Skuladottir H, Wilcox A, McConnaughey R et al. First-trimester nonsystemic

corticosteroid use and the risk of oral clefts in Norway. Ann Epidemiol 2014; 24:

635-40.

58 Skuladottir H, Wilcox AJ, Ma C et al. Corticosteroid use and risk of orofacial

clefts. Birth Defects Res A Clin Mol Teratol 2014; 100: 499-506.

59 Chi CC, Mayon-White RT, Wojnarowska FT. Safety of topical corticosteroids in

pregnancy: a population-based cohort study. J Invest Dermatol 2011; 131: 884-

91.

60 Chi CC, Wang SH, Mayon-White R et al. Pregnancy outcomes after maternal

exposure to topical corticosteroids: a UK population-based cohort study. JAMA

Dermatol 2013; 149: 1274-80.

61 Edwards MJ, Agho K, Attia J et al. Case-control study of cleft lip or palate after

maternal use of topical corticosteroids during pregnancy. Am J Med Genet A

2003; 120: 459-63.

62 Hviid A, Molgaard-Nielsen D. Corticosteroid use during pregnancy and risk of

orofacial clefts. CMAJ 2011; 183: 796-804.

63 Mahé A, Perret JL, Ly F et al. The cosmetic use of skin-lightening products

during pregnancy in Dakar, Senegal: a common and potentially hazardous

practice. Trans R Soc Trop Med Hyg 2007; 101: 183-7.

64 Park-Wyllie L, Mazzotta P, Pastuszak A et al. Birth defects after maternal

exposure to corticosteroids: prospective cohort study and meta-analysis of

epidemiological studies. Teratology 2000; 62: 385-92.

23

65 Gur C, Diav-Citrin O, Shechtman S et al. Pregnancy outcome after first trimester

exposure to corticosteroids: a prospective controlled study. Reprod Toxicol 2004;

18: 93-101.

66 Mehta DK, ed. British National Formulary, 53rd edn. London: BMJ Publishing

Group Ltd and RPS Publishing. 2007.

24

Table 1 Levels of evidence defined by the Oxford Centre for Evidence-Based Medicine

Level 1 Systematic review of randomised trials or n-of-1 trial

Level 2 Randomised trial or (exceptionally) observational study with dramatic effect

Level 3

Non-randomized controlled cohort/follow-up study (post-marketing surveillance)

provided there are sufficient numbers to rule out a common harm. (For long-term

harms the duration of follow-up must be sufficient.)**

Level 4 Case-series, case-control, or historically controlled studies**

Level 5 Mechanism-based reasoning

* Level may be graded down on the basis of study quality, imprecision, indirectness

(study PICO does not match questions PICO), because of inconsistency between studies,

or because the absolute effect size is very small; Level may be graded up if there is a

large or very large effect size.

** As always, a systematic review is generally better than an individual study.

25

Table 2 Grades of recommendation defined by the GRADE Working Group

High We are very confident that the true effect lies close to that of the estimate of

the effect

Moderate

We are moderately confident in the effect estimate: The true effect is likely

to be close to the estimate of the effect, but there is a possibility that it is

substantially different

Low Our confidence in the effect estimate is limited: The true effect may be

substantially different from the estimate of the effect

Very low We have very little confidence in the effect estimate: The true effect is likely

to be substantially different from the estimate of effect

The quality of evidence from randomised trials is initially rated as high and observational

studies as low. Further evaluation may upgrade the quality of evidence for large

magnitude effect, dose response, and confounders likely minimise the effect, and may

downgrade due to study limitations, imprecision, inconsistency of results, indirectness of

evidence and publication bias.

26

Table 3 Placental metabolism and transfer of various corticosteroids

Metabolised by placental 11β-

hydroxysteroid dehydrogenase Placental transfer

Prednisolone 10-12%

Hydrocortisone 85% 15%

Betamethasone 28-33%

Methylprednisolone 44.6%

Dexamethasone 67%

Fluticasone 0%

In summary, it is difficult to predict the effects of topically applied corticosteroid used by

the mother on the unborn child, as there are so many independent factors. Clinical trials

are unethical and therefore have never been conducted.

27

Table 4 Studies on the safety of topical corticosteroids in pregnancy

First author;

publication

year; country;

funding

source

Study design

Setting

Number of participants

Ascertainment of exposure

Outcome measures Results

Czeizel; 1997;

Hungary; not

reported

Case-control

study

Population-

based, using

the dataset

Hungarian

Case-Control

Surveillance of

Congenital

Abnormalities

20,830 cases of congenital

abnormalities, 35,727 controls

Prenatal log book, questionnaire and

interview

Adjusted OR with 95% CI of

maternal ointment

corticosteroid treatment in 14

congenital abnormalities group

An association between cleft lip ± palate and

maternal corticosteroid ointment treatment in the

whole pregnancy [adjusted OR 2.21 (95% CI 1.11-

4.39)] and in the 1st month of gestation [OR 4.19

(95% CI 1.47-11.97)] was revealed. However, the

adjusted OR was not significant in the 2nd and 3rd

months of gestation, which are the critical period

for congenital abnormalities (but the OR statistic

was not reported). Also, no significant association

between maternal corticosteroid ointment use and

other major or mild congenital abnormalities was

found.

Mygind; 2002;

Denmark;

Western Danish

Research Forum

for Health

Sciences, Danish

Medical

Research

Council, and

Foundation of

Hørslev

Retrospective

cohort study

Based on local

population in

North Jutland,

using Danish

Medical Birth

registry

363 primiparous, singleton pregnant

women exposed to topical

corticosteroids within 30 days before

conception and/or during pregnancy,

9263 controls receiving no

prescriptions

Pharmaco-epidemiological prescription

database

Crude and adjusted OR with

95% CI for low birth weight,

malformations, preterm

delivery, and stillbirth

No increased risk of low birth weight,

malformations, preterm delivery and stillbirth

among the exposure group. The adjusted OR (95%

CI) for low birth weight, malformations and

preterm delivery among women receiving

weak/medium strong corticosteroids were 0.7

(0.17–2.85), 0.93 (0.23–3.80) and 1.04 (0.56–

1.92), respectively, and those of strong/very strong

corticosteroids were 1.23 (0.45–3.37), 0.56 (0.14–

2.28) and 0.99 (0.54–1.84), respectively. The

crude OR for stillbirth among women receiving

prescription of topical corticosteroid during

pregnancy was 2.6 (95% CI 0.83-8.05).

Edwards; 2003;

Australia; not

reported

Case-control

study

Single teaching

hospital

48 cases with nonsyndromic cleft lip or

palate, 58 controls

Retrospective interview

OR with 95% CI of topical

corticosteroid use in the first

trimester of pregnancy for

cleft lip or palate, using

univariate and multiple

regression analysis

A significant increase in the prevalence of

maternal first-trimester use of topical

corticosteroid among cases with syndromic cleft

[adjusted OR 18.6 (95% CI 1.29–270), p = 0.032]

Källén; 2003;

Sweden; KA

Wallenberg

Foundation.

Register

analysis

Population-

based, Swedish

Medical Birth

Registry

149,932 women with first-trimester

drug exposure, containing

1094 exposed to topical corticosteroid

Prospective interview at the first

antenatal care visit (usually week 10 to

12)

Expected number of cases

with orofacial cleft, compared

with observed number as risk

ratio (RR; observed/expected)

with 95% CI based on exact

Poisson distribution

No significant association between topical

corticosteroid use in the first trimester of

pregnancy and orofacial clefts [RR 2.01 (95% CI

0.55-5.15)].

28

Pradat; 2003;

multi-national;

not reported

Case-control

study

Multi-centric

database,

Malformation

Drug Exposure

Surveillance

11,150 cases with congenital

malformations, containing 982 cases of

cleft palate or lip

Reported by participating researchers

Mantel-Haenszel OR with

95% CI after stratification by

registry

No correlations of first-trimester exposure to

topical corticosteroids with cleft palate or lip [OR

0.52 (95% CI 0.16-1.64)], cleft palate [OR 0 (95%

CI 0-3.41)], and cleft lip ± palate [OR 0.73 (95%

CI 0.23-2.37)].

Mahé; 2007;

Senegal; not

reported

Cohort study

Single

maternity

hospital

34 of 99 women with exposure to

potent topical corticosteroids (28

clobetasol propionate, 60 g/month).

Compared to non users of very potent

topical corticosteroids

Interviewed at 6-9 months pregnancy,

local area only

Plasma cortisol, Pregnancy

outcome: mode of delivery,

gestational age, birth weight,

placental weight, status of

newborn and mother.

χ2 and Fischer’s two tailed

exact test, Kruskall-Wallis H

test.

Increased frequency of mild vaginal bleeding (p =

0.031), decreased birth weight (P = 0.046),

decreased placental weight (P = 0.043), decreased

placental cortisol (P = 0.07).

Carmichael;

2007; US;

Center for

Disease Control

and Prevention

Case-control

study

Multistate, part

of the National

Birth Defects

Prevention

Study

1110 infants with cleft lip ± cleft palate

and 4079 control infants

Maternal interviews were conducted

with a standardized, computer-based

telephone questionnaire in English or

Spanish, no earlier than 6 weeks and no

later than 24 months after the infant’s

estimated date of delivery

OR with 95% CI of maternal

use of topical corticosteroids

confirmed by clinical

description or surgical or

autopsy report. Each case

received an additional review

by 1 clinical geneticist to

ensure that cases from each

study centre met standard

eligibility criteria.

No significant association between cleft lip ± cleft

palate and maternal use of topical corticosteroids

from 4 weeks before through 12 weeks after

conception [OR 0.9 (95% CI 0.2-4.3)]

Carmichael;

2009; US;

Center for

Disease Control

and Prevention

Case-control

study

Multistate, part

of the National

Birth Defects

Prevention

Study

1165 cases of second- or third-degree

hypospadias and 3000 non-malformed

controls

Maternal interviews were conducted

using a standardized, computer-based

telephone questionnaire in English or

Spanish, no earlier than 6 weeks and no

later than 24 months after the infant’s

estimated date of delivery

OR with 95% CI of maternal

use of topical corticosteroids

confirmed by clinical

description or operative report.

Each case received an

additional review by 1 clinical

geneticist to ensure that cases

from each study centre met

standard eligibility criteria.

No significant association between hypospadias

and maternal use of topical corticosteroids from 4

weeks before through 18 weeks after conception

[OR 0.37 (95% CI 0.12, 1.17)]

Chi; 2011; UK;

British Skin

Foundation and

University of

Oxford

Retrospective

cohort study

Population-

based

35,503 pregnant women prescribed

topical corticosteroids during the period

from 85 days before last menstrual

period to delivery or fetal death and

48,630 unexposed women

Prescription records

Adjusted RR for orofacial cleft

(and its two categories, cleft

lip ± palate and isolated cleft

palate), fetal growth

restriction, preterm delivery,

and fetal death

A significant association of maternal exposure to

potent/very potent topical corticosteroids with

fetal growth restriction [adjusted RR 2.08 (95% CI

1.40-3.10)]. No significant association of topical

corticosteroids of any potency with other

pregnancy outcomes.

29

Hviid; 2011;

Denmark;

Danish Medical

Research

Council and

Lundbeck

Foundation

Retrospective

cohort study

Nationwide

22,480 pregnant women filled

prescriptions for topical corticosteroids

during the first trimester and 810,156

controls receiving no prescriptions for

topical corticosteroids

Danish Prescription Drug Register

Adjusted OR with 95% CI of

cleft lip ± palate and isolated

cleft palate

A significant association of topical corticosteroid

use during first trimester and cleft lip ± palate

[adjusted OR 1.45 (95% CI 1.03-2.05)]. However,

exploratory analyses of the dose-response and

potency-response relations did not support a

causal association. The observed association may

arise from multiple comparisons.

Chi; 2013; UK;

Wellbeing of

Women and

Chang Gung

Memorial

Hospital, Chiayi

Retrospective

cohort study

Population-

based

2658 pregnant women exposed to

topical corticosteroid and 7246

unexposed pregnant women.

Adjusted RR with 95% CI for

orofacial cleft, low birth

weight, preterm delivery, fetal

death, and low Apgar score as

well as mode of delivery

A significantly increased risk of low birth weight

when the dispensed amount of potent or very

potent topical corticosteroids exceeded 300 g

during the entire pregnancy [adjusted RR, 7.74

(95%CI, 1.49-40.11)]. No associations of maternal

topical corticosteroid exposure with orofacial

cleft, preterm delivery, fetal death, low Apgar

score, and mode of delivery.

Skuladottir;

2014; US;

Centers for

Disease Control

and Prevention

Case-control

study

Population-

based

2372 cleft cases (1577 infants with cleft

lip ± palate and 795 infants with cleft

palate alone) and 5922 controls without

major congenital malformations

randomly selected from birth

certificates or birth hospitals

Adjusted OR with 95% CI of

maternal use of topical

corticosteroids during the

periconceptional period

The overall association of corticosteroids and cleft

lip and palate was 1.0 (95% CI, 0.7–1.4).

Skuladottir;

2014; US;

Centers for

Disease Control

and Prevention

Case-control

study

Population-

based

123 cases with cleft lip ± palate and 61

with cleft palate alone identified

through the Medical Birth Registry of

Norway, and 551 control mothers

randomly selected from the Norwegian

Mother and Child Cohort Study

Adjusted OR with 95% CI of

maternal use of topical

corticosteroids during the

periconceptional period

No associations for any cleft type [adjusted OR,

1.0 (95% CI 0.5‒2.2), cleft lip ± palate [adjusted

OR 1.2 (95% CI 0.5‒2.9) nor for cleft palate alone

[adjusted OR 0.6 (95% CI 0.1‒2.6).

Skuladottir;

2014; Norway;

Western

Norwegian

Health

Authorities

Case-control

study

2 specialised

surgical centres

for oral cleft in

Norway

573 cleft cases (377 infants with cleft

lip ± palate and 196 infants with cleft

palate alone) and 763 controls without

major congenital malformations

randomly selected from the Medical

Birth Registry of Norway

Adjusted OR with 95% CI of

maternal first-trimester

exposure to corticosteroids

No significant associations of first-trimester use of

topical corticosteroids with both cleft lip ± palate

(adjusted OR 2.3 ( 95% CI 0.71‒7.7) and cleft

palate alone (adjusted OR, 3.4; CI 0.87‒13)

CI, confidence interval; OR, odds ratio; RR, risk ratio.

30

Table 5 Potency of topical corticosteroids (adapted from the British National Formulary

66 and Chi’s thesis9)

Potency Topical corticosteroids

Mild to moderate Alclometasone dipropionate 0.05%

Betamethasone valerate 0.025%

Clobetasone butyrate 0.05%

Fludroxycortide (flurandrenolone) 0.0125%

Fluocinolone acetonide 0.00625%

Fluocortolone 0.25%

Hydrocortisone 0.1–2.5%

Potent to very potent Betamethasone dipropionate 0.05-0.064%

Betamethasone valerate 0.1-0.12%

Clobetasol propionate 0.05%

Diflucortolone valerate 0.1-0.3%

Fluocinolone acetonide 0.025%

Fluocinonide 0.05%

*Fluticasone propionate 0.005-0.05%

*Hydrocortisone butyrate 0.1%

*Mometasone furoate 0.1%

*Methylprednisolone aceponate 0.1%

Triamcinolone acetonide 0.1%

*The drugs have high potency based on efficacy but fewer adverse effects37,39 (see Figure

1).

31

Figure 1 Therapeutic index of topical corticosteroids (modified from Luger TA et al

200439). BMV, betamethasone valerate; CP, clobetasol propionate; HC, hydrocortisone;

HCB, hydrocortisone butyrate; MF, mometasone furoate; MPA, methylprednisolone

acetate; PC, prednicarbate; TRI, triamcinolone acetonide.

Conflicts of interests The Work Under Consideration for Publication Aberer Chi Gabbud Haustein 1 Grant None None None None 2 Consulting fee or

honorarium None None None None

3 Support for travel to meetings for the study or other purposes

None None None None

4 Fees for participation in review activities, such as data monitoring boards, statistical analysis, end point committees, and the like

None None None None

5 Payment for writing or reviewing the manuscript

None None None None

6 Provision of writing assistance, medicines, equipment, or administrative support

None None None None

7 Other None None None None * This means money that your institution received for your efforts on this study. Relevant financial activities outside the submitted work Aberer Chi Gabbud Haustein 1 Board membership None None None None 2 Consultancy None Received fees

for speaking from Johnson & Johnson Taiwan Ltd, and Pfizer Inc

None None

3 Employment None None Retired from private practice

None

4 Expert testimony None None None None 5 Grants/grants

pending None None None None

6 Payment for lectures including service on speakers bureaus

None Received fees for speaking from Eisai Taiwan Inc, Johnson & Johnson Taiwan Ltd, and Pfizer Taiwan Inc

None None

7 Payment for manuscript preparation

None None None None

8 Patents (planned, pending or issued)

None None None None

9 Royalties None None None None 10 Payment for

development of educational presentations

None None None None

11 Stock/stock options None None None None 12 Travel/accommodati

ons/meeting expenses unrelated to activities listed**

None None None None

13 Other (err on the side of full disclosure)

None None None None

* This means money that your institution received for your efforts. ** For example, if you report a consultancy above there is no need to report travel related to that consultancy on this line. Other relationships Aberer Chi Gabbud Haustein

1 Are there other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing, what you wrote in the submitted work?

None None None None

Conflicts of interests The Work Under Consideration for Publication Karpati Kirtschig Lipozencic Wojnarowska Zuberbier 1 Grant None None None None None 2 Consulting fee or

honorarium None None None None None

3 Support for travel to meetings for the study or other purposes

None None None None None

4 Fees for participation in review activities, such as data monitoring boards, statistical analysis, end point committees, and the like

None None None None None

5 Payment for writing or reviewing the manuscript

None None None None None

6 Provision of writing assistance, medicines, equipment, or administrative support

None None None None None

7 Other None None None None None * This means money that your institution received for your efforts on this study. Relevant financial activities outside the submitted work Karpati Kirtschig Lipozencic Wojnarowska Zuberbier

1 Board membership None None None None None 2 Consultancy None None None None s. list attached 3 Employment None None None None None 4 Expert testimony None None None None None 5 Grants/grants

pending None None None None s. list attached

6 Payment for lectures including service on speakers bureaus

None None None None s. list attached

7 Payment for manuscript preparation

None None None None None

8 Patents (planned, pending or issued)

None None None None None

9 Royalties None None None None None 10

Payment for development of educational presentations

None None None None None

11

Stock/stock options None None None None None

12

Travel/accommodations/meeting expenses unrelated to activities listed**

None None None None None

13

Other (err on the side of full disclosure)

None None None None None

* This means money that your institution received for your efforts. ** For example, if you report a consultancy above there is no need to report travel related to that consultancy on this line. Other relationships

Karpati Kirtschig Lipozencic Wojnarowska Zuberbier 1 Are there other

relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing, what you wrote in the submitted work?

None None None None None

T:\Dokumente\CoI ‐ Conflict of interests TZ ‐ 2015 2016\CoI ‐ General Disclosure of possible conflict of interest ‐ Torsten Zuberbier ‐ NEU ‐ 180316.docx 25. April 2016 

  

Torsten Zuberbier, MD  

Contact details/affiliation:   

Department of Dermatology and Allergy  

Allergy Centre Charité  

Charité ‐Universitätsmedizin Berlin  

Charitéplatz 1 / 10117 Berlin, Germany  

Phone +4930450518 135/ Fax 49 30 450518919  

Email: torsten.zuberbier@charite.de  

DISCLOSURE OF POSSIBLE CONFLICT OF INTEREST  

 Industry consulting, research grants and/or honoraria:   

Consulting with the following companies: ALK, Almirall, Abbvie, Astellas, Bayer Health Care, Bencard, 

Berlin Chemie, FAES, HAL, Henkel, Kryolan, Leti, Meda, Menarini, Merck, MSD, Novartis, 

Pharmasquire, Quintiles, Serono, Stallergenes, Takeda, Teva, UCB  

Organizational Affiliations:   

Committee member, WHO‐Initiative “Allergic Rhinitis and its Impact on Asthma” (ARIA) 

Member of the Board, German Society for Allergy and Clinical Immunology (DGAKI) 

Head, European Centre for Allergy Research Foundation (ECARF) 

Secretary General , Global Allergy and Asthma European Network (GA²LEN) 

Member, Committee on Allergy Diagnosis and Molecular Allergology, World Allergy Organisation (WAO) 

 

Prof. Dr. med. Dr. h. c. Torsten Zuberbier